HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity.
BACKGROUND
Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain.


RESULTS
The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain.


CONCLUSIONS
Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.
Eid
Samer R
SR
Department of Pain Research, Neuroscience Drug Discovery, Merck Research Laboratories, West Point, Philadelphia, USA. samer_eid@merck.com
Crown
Eric D
ED
Moore
Eric L
EL
Liang
Hongyu A
HA
Choong
Kar-Chan
KC
Dima
Shelley
S
Henze
Darrell A
DA
Kane
Stefanie A
SA
Urban
Mark O
MO
D000083:Acetanilides / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D017487:Ankyrins; D015220:Calcium Channels / Q000502:physiology*; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*
C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D000700:Analgesics; D017487:Ankyrins; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D011687:Purines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat